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Aberrant Caspase Activation in Laminin-?2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity.

ABSTRACT: BACKGROUND:Mutations in the LAMA2 gene encoding laminin-?2 cause congenital muscular dystrophy Type 1A (MDC1A), a severe recessive disease with no effective treatment. Previous studies have shown that aberrant activation of caspases and cell death through a pathway regulated by BAX and KU70 is a significant contributor to pathogenesis in laminin-?2-deficiency. OBJECTIVES:To identify mechanisms of pathogenesis in MDC1A. METHODS:We used immunocytochemical and molecular studies of human myogenic cells and mouse muscles-comparing laminin-?2-deficient vs. healthy controls-to identify mechanisms that regulate pathological activation of caspase in laminin-?2-deficiency. RESULTS:In cultures of myogenic cells from MDC1A donors, p53 accumulated in a subset of nuclei and aberrant caspase activation was inhibited by the p53 inhibitor pifithrin-alpha. Also, the p53 target BBC3 (PUMA) was upregulated in both MDC1A myogenic cells and Lama2-/- mouse muscles. In addition, studies with sirtuin inhibitors and SIRT1 overexpression showed that caspase activation in MDC1A myotubes was inversely related to sirtuin deacetylase activity. Caspase activation in laminin-?2-deficiency was, however, not associated with increased phosphorylation of p38 MAPK. CONCLUSIONS:Aberrant caspase activation in MDC1A cells was mediated both by sirtuin deacetylase activity and by p53. Interventions that inhibit aberrant caspase activation by targeting sirtuin or p53 function could potentially be useful in ameliorating MDC1A.

SUBMITTER: Yoon S

PROVIDER: S-EPMC5836413 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Aberrant Caspase Activation in Laminin-α2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity.

Yoon Soonsang S Beermann Mary Lou ML Yu Bryant B Shao Di D Bachschmid Markus M Miller Jeffrey Boone JB

Journal of neuromuscular diseases 20180101 1

<h4>Background</h4>Mutations in the LAMA2 gene encoding laminin-α2 cause congenital muscular dystrophy Type 1A (MDC1A), a severe recessive disease with no effective treatment. Previous studies have shown that aberrant activation of caspases and cell death through a pathway regulated by BAX and KU70 is a significant contributor to pathogenesis in laminin-α2-deficiency.<h4>Objectives</h4>To identify mechanisms of pathogenesis in MDC1A.<h4>Methods</h4>We used immunocytochemical and molecular studie ...[more]

PMID: 29278895

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Project description:ObjectiveThe role of receptors for endogenous metabolic danger signals-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for danger signals-associated molecular patterns to initiation of inflammation in bone marrow-derived cells, such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating danger signals-associated molecular patterns in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation.Approach and resultsUsing biochemical, immunologic, pathological, and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)(-/-)/caspase-1(-/-) double knockout mice, we made the following observations: (1) early hyperlipidemia induced caspase-1 activation in ApoE(-/-) mouse aorta; (2) caspase-1(-/-)/ApoE(-/-) mice attenuated early atherosclerosis; (3) caspase-1(-/-)/ApoE(-/-) mice had decreased aortic expression of proinflammatory cytokines and attenuated aortic monocyte recruitment; and (4) caspase-1(-/-)/ApoE(-/-) mice had decreased EC activation, including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a reactive oxygen species mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 in the ApoE(-/-) aorta, and sirtuin 1 inhibited caspase-1 upregulated genes via activator protein-1 pathway.ConclusionsOur results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-sirtuin 1-activator protein-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations.

Dataset Information

Aberrant Caspase Activation in Laminin-?2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity.

Publications

Aberrant Caspase Activation in Laminin-α2-Deficient Human Myogenic Cells is Mediated by p53 and Sirtuin Activity.

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